MODY3, renal cysts, and Dandy-Walker variants with a microdeletion spanning the HNF1A gene

Area of Science:

• Genetics
• Endocrinology
• Developmental Biology

Background:

• Heterozygous mutations in the hepatocyte nuclear factor-1-α (HNF1A) gene are the primary cause of maturity-onset diabetes of the young (MODY), typically without extrahepatic manifestations.
• Renal cysts and diabetes syndrome are linked to HNF1B mutations, while associations between MODY3 and Dandy-Walker variants (DWV) are unreported.
• HNF1A mutations are suspected contributors to renal malformations.

Observation:

• A Japanese girl presented with glycosuria, developmental delay, intellectual disability, renal cysts, and DWV.
• Genetic analysis revealed no HNF1B mutations.
• Array comparative genomic hybridization identified a de novo 5.6 Mb deletion at 12q24.22-q24.31, encompassing the HNF1A gene.

Findings:

• The identified deletion is consistent with a diagnosis of MODY3.
• The diverse clinical presentation suggests a novel microdeletion syndrome associated with the HNF1A gene.
• Haploinsufficiency of HNF1A may interact with specific HNF1B haplotypes, potentially leading to renal cysts via a truncated heterodimer.

Implications:

• This case highlights a potential link between HNF1A deletions and renal malformations, expanding the known phenotype of MODY3.
• Further evaluation of patients with 12q24.31 deletions is crucial for establishing genotype-phenotype correlations.
• Elucidating this emerging microdeletion syndrome could improve diagnosis and management of related genetic disorders.